ABSTRACT
In the first part of a series of studies to account for perfluorooctane sulfonate (PFOS)-induced sheep red blood cell (SRBC)-specific immunoglobulin M (IgM) antibody suppression in mice, a survey of clinical and immunotoxicological endpoints was examined. Adult female B6C3F1 mice were exposed orally for 28 days to a total administered dose (TAD) of 0, 0.1, 0.5, 1, or 5 mg PFOS/kg. Uterus wet weight was significantly decreased compared with control at the 5 mg/kg dose. No indications of wasting syndrome, malnutrition, alteration of thyroid homeostasis, or signs of overt toxicity were observed. Numbers of splenic CD19+/CD21â», CD19+/CD21+, B220+/CD40+, CD4+/CD154â», CD4+/CD154+, and MHC-II+ cells were not altered. Additionally, ex vivo interleukin-4 (IL-4), IL-5, and IL-6 production by in vitro anti-CD3- or phorbol myristate acetate-stimulated CD4+ T-cells was not affected. Ex vivo IL-6 production by B-cells was significantly increased by in vitro stimulation with either anti-CD40 or lipopolysaccharide. Increased IL-6 production by B-cells was the most sensitive endpoint assessed resulting in alterations at the lowest dose tested (0.1 mg/kg TAD) following anti-CD40 stimulation. Further studies are required to characterize effects on inflammatory markers such as IL-6 at environmentally relevant concentrations of PFOS and to determine the key events associated with PFOS-induced IgM suppression to address potential human health risks.
Subject(s)
Alkanesulfonic Acids/toxicity , B-Lymphocytes/drug effects , Environmental Pollutants/toxicity , Fluorocarbons/toxicity , Immunoglobulin M/immunology , Interleukin-6/immunology , Alkanesulfonic Acids/blood , Alkanesulfonic Acids/pharmacokinetics , Animals , Antigens, CD/immunology , B-Lymphocytes/immunology , Body Weight/drug effects , Dose-Response Relationship, Drug , Environmental Pollutants/blood , Environmental Pollutants/pharmacokinetics , Enzyme-Linked Immunosorbent Assay , Female , Fluorocarbons/blood , Fluorocarbons/pharmacokinetics , Immunoglobulin M/blood , Interleukin-6/biosynthesis , Liver/metabolism , Mice , Mice, Inbred Strains , Organ Size/drug effects , Spleen/drug effects , Spleen/immunology , Spleen/pathology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Thyroid Hormones/blood , Tissue DistributionABSTRACT
Perfluorooctane sulfonate (PFOS; 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluoro-1-octanesulfonic acid) has been reported to alter humoral immune functions, but inflammatory processes following PFOS exposure have not been fully characterized. Therefore, the current study, assessed TNF-α and IL-6 concentrations in serum and peritoneal lavage fluid, numbers of splenoctyes expressing intracellular TNF-α, IL-6, IL-10 or IL-1, and ex vivo TNF-α and IL-6 production by peritoneal macrophages following either in vivo or in vitro LPS exposure. Adult female B6C3F1 mice were exposed orally for 28 days to 0, 1, 3, or 300 mg PFOS/kg total administered dose [TAD] (e.g., 0, 0.0331, 0.0993 or 9.93 mg/kg/day). Body and spleen masses were significantly reduced in the highest PFOS treatment group compared to the control group, whereas liver mass was significantly increased. Serum TNF-α levels were significantly decreased following exposure to 1 mg PFOS/kg TAD as compared to controls, while serum IL-6 levels were increased. IL-6 concentrations in peritoneal lavage fluid decreased with increasing dose. PFOS treatment did not alter numbers of splenocytes expressing intracellular levels of TNF-α, IL-10 or IL-1. Numbers of splenocytes expressing intracellular levels of IL-6 were significantly decreased in the 3 mg/kg treatment as compared to controls. Overall, these data suggest that PFOS exposure can alter some inflammatory processes, which could potentially lead to misdirected inflammatory responses.
Subject(s)
Alkanesulfonic Acids/toxicity , Environmental Pollutants/toxicity , Fluorocarbons/toxicity , Inflammation/chemically induced , Interleukin-6/analysis , Lipopolysaccharides/toxicity , Tumor Necrosis Factor-alpha/analysis , Animals , Ascitic Fluid/chemistry , Ascitic Fluid/cytology , Ascitic Fluid/immunology , Biomarkers/analysis , Biomarkers/blood , Body Weight/drug effects , Cell Count , Dose-Response Relationship, Drug , Female , Inflammation/immunology , Interleukin-6/blood , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/immunology , Mice , Mice, Inbred Strains , Organ Size/drug effects , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Tumor Necrosis Factor-alpha/bloodABSTRACT
The bioactive lipid sphingosine-1-phosphate (S1P) is emerging as an important mediator of immune and inflammatory responses. S1P formation is catalyzed by sphingosine kinase (SK), of which the SK1 isoenzyme is activated by tumor necrosis alpha (TNF-alpha). SK1 has been shown to be required for mediating TNF-alpha inflammatory responses in cells, including induction of cyclooxygenase 2 (COX-2). Because TNF-alpha and COX-2 are increased in patients with inflammatory bowel disease (IBD), we investigated the role of SK1 in a murine model of colitis. SK1(-/-) mice treated with dextran sulfate sodium (DSS) had significantly less blood loss, weight loss, colon shortening, colon histological damage, and splenomegaly than did wild-type (WT) mice. In addition, SK1(-/-) mice had no systemic inflammatory response. Moreover, WT but not SK1(-/-) mice treated with dextran sulfate sodium had significant increases in blood S1P levels, colon SK1 message and activity, and colon neutrophilic infiltrate. Unlike WT mice, SK1(-/-) mice failed to show colonic COX-2 induction despite an exaggerated TNF-alpha response; thus implicating for the first time SK1 in TNF-alpha-mediated COX-2 induction in vivo. Inhibition of SK1 may prove to be a valuable therapeutic target by inhibiting systemic and local inflammation in IBD.
